pH-Responsive Carboxymethyl Cellulose-Encapsulating Hesperidin-Selenium Nanoparticles Attenuate Paracetamol-Induced Acute Kidney Injury via Keap-1/Nrf2, NF-κB, and Mitochondrial Apoptosis Modulation.

Oligodendrocytes (OLs) are glial cells in the central nervous system (CNS) that produce myelin, a lipid-rich membrane that wraps around axons to provide metabolic and trophic support and increase action potential velocity. A single OL can myelinate dozens of axons simultaneously, including different classes of axons defined by distinct neurotransmission profiles. Because different neuron types have different axon lengths, firing rates, and energetic demands, differences in the amount and composition of myelin on axons potentially contribute to the functions of distinct neural circuits. Therefore, OLs and their myelin sheaths may be uniquely positioned to modulate neural circuit output by regulating the timing, strength, or frequency of circuit signals. Neural circuits require a balance of excitatory and inhibitory influences to achieve regulated output, such as the coordinated locomotion generated by the spinal cord. Canonically, glutamatergic neurons provide excitatory input and γ-amino butyric (GABAergic) and glycinergic neurons provide inhibitory influence on circuit output. Critically, glutamatergic, GABAergic, and glycinergic neurons signal through unique molecular machinery where their axon terminals create synapses with the appropriate postsynaptic terminal. Postsynaptic scaffold proteins provide specificity for synapse formation by anchoring receptors and cell adhesion molecules that are enriched at unique synapses. Postsynaptic Density 95 protein (PSD95) is the primary scaffold protein at excitatory glutamatergic synapses, whereas Gephyrin (Gphn) is the postsynaptic scaffold at inhibitory GABAergic and glycinergic synapses. This specificity of synaptic communication is necessary in complex circuits to coordinate neuronal firing and generate functional behaviors such as locomotion. Remarkably, OLs produce myelin sheaths with variable lengths and thicknesses on individual axons, and myelin patterns on distinct classes of axons vary across neuron type and brain region. What mechanisms might convey specificity in myelin formation on distinct axon classes? One possibility is that OLs engage with axons using mechanisms similar to synapse formation, where a myelin sheath contacts an axon at an axo-sheath interface. Several findings support this possibility. First, neuronal activity promotes myelin formation through vesicle release along the axon. This vesicular release is accompanied by axonal Ca events at sites where myelin growth will subsequently occur. Second, gene expression profiling studies show that OL lineage cells (OLCs) express many genes that encode postsynaptic proteins such as PSD95 and Gphn. Third, interfering with postsynaptic protein function in OLs disrupts myelin formation and maintenance. And fourth, an OL precursor cell (OPC)-specific knockout of GABAR γ2 altered myelin profiles on fast-spiking, GABAergic PV interneurons and their subsequent firing rate without impacting the myelin or firing rate of neighboring, glutamatergic spiny stellate cell interneurons. Thus, we sought to understand whether distinct axon classes use unique mechanisms for myelination. To this end, we hypothesized that OLs and their individual myelin sheaths use postsynaptic signaling machinery to coordinate axon identity-dependent myelination.